3-ethylenedioxy-6-alkylpregn-5-en-17-hydroxy-20-one and derivatives thereof



United States Patent 3,248,391 3-ETHYLENEDIOXY-6-ALKYLPREGN-5-EN-17-HY-DROXY-ZO-ONE AND DERIVATIVES THEREOF Bjarte Liiken, 44 Edgewood Road,Shrewsbury, Mass., and Irving V. Sollins, 87 Brevoort Lane, Rye, N.Y. NoDrawing. Filed Nov. 29, 1963, Ser. No. 327,072 5 Claims. (Cl. 260-43955)The present invention relates to B-ethylene dioxy-6-alkylpregn-S-en-7-hydroxy-20-one, the 17 acyloxy and the 2 l-fluoroderivatives thereof. These compounds possess pr-o'gestational,antiandrogenic and antiestrogenic activity. They are highly potentorally active hormonal agents. In many respects these compounds surpass,in activity, the known orally active compounds having the same 6 andl7-substituents but characterized by a A ketone structure.

More generally, the compounds of the present invention can berepresented by the following structural formula:

wherein X is H or F; Y is methyl, ethyl or propyl, and wherein R is H ora lower acyl group. The hydrocarbon chain of the 8 or less carbon acylgroup (R) can be straight chain or branched alkyl radicals such asmethyl, ethyl, propyl, isopropyl, nibutyl, isobutyl, tertiary butyl,n-pentyl, neopentyl, etc. The hydrocanb on chain may also be acycloaliphatic radical such as cyclopenty-l, cyclohexyl, cyclopentylmethyl, cyclohexyl methyl and the like.

The cyclic ketal at the 3-position is ethylene dioxy, 1,2, propylenedioxy 1, 2, or 2, 3 butylene dioxy.

The high oral activity of the present compounds appears to be intimatelyrelated to the 3+ketal A -alkyl structure. Comparative tests on thecorresponding compounds not having a 6-alkyl group showed an absence ofthe high activity. On the other hand, comparative tests made with theunketalized precursor derivatives, i.e. the 3 keto A steroids, showedthe present compounds to be more active orally than the precursors.

The compounds of the present invention can be prepared from thecorresponding A -keto-6-alkyl steroids by known ketalization techniquessuch as is described in:

(l) Antonucci et al., J. Organic Chem, 17, 1369 (1952) (2) Dauben etal., I. Am. Chem. Soc., 7 6, 1359 (1954) The present invention isfurther described in the examples which follow, which examples are to beconsidered illustrative only and not as limiting the invention in spiritor scope.

Example I I sulfate, and the solvent (benzene) was removed byevaporation under reduced pressure. To the crystalline residue 3,248,391Patented Apr. 26, 1966 Was added l5-20 parts of ether, and the slurryfiltered. There remained 4.0 parts of 17a-a-cetoxy-3-ethy1enedioxy-6-methylpregn-5-en-20-one, which after recrystallization melted at aboutl8 7l89 C. and had a specific optical rotation of about 48.5 inchloroform solution (1 g./ ml.). The infrared spectrum shows maxima at3.40, 5.77, 5.86, 7.92, 8.00, 9.10, 9.30, 9.8 3 and 10.33 microns. Teststudies indicate that this compound may have a higher antiestrogenactivity than 6ix-methyl 17-acetoxy progesterone. It also exhibits highprogestational activity and a high antiandrogen activity.

Example II.17 x-hydr0xy 3-etlzylene dioxy-o-methylpregn-S-en-ZO-one To asolution of 10 parts of l7u-hydroxy-6a-methylprogesterone in 300 partsof 2-methyl-2-ethyl-l,3-dioxolane was added 0.12 part Of ptoluenesulfonic acid monohydrate, and the mixture heated in a flaskequipped with a packed column having a total reflux partial take-offhead corresponding to approximately 40 theoretical plates under totalreflux. The mixture was heated to boiling and the reflux ratiomaintained at about 1:60 for a period of 24 hours. Initially thetemperature at the top of the column was 79 C. corresponding to theboiling point of b'utanone, formed 'by the exchange reaction (and whichis continuously removed). At the end of the reaction period the boilingpoint temperature at the top of the column was 116 0, indicating thatthe distillate was essentially 2-methyl-2-ethylal.3-dioxolane and thatthe reaction was completed.

The solution was cooled, transferred to a separatory funnel and washedtwice with 100 parts each of 2 N, SO'dlUIITl carbonate solution. Themethyl ethyl dioxolane layer was dried over anhydrous sodium sulfate andthe solvent removed by evaporation under reduced pressure. The residuewas dissolved in 250 parts of methanol containing traces (0.01 part) ofdiethylamine. Filtration through celite, followed by concentration underreduced pressure to a final volume of about 60 parts, cooling andfiltration, gave 8.3 parts of crystals; further concentration of themother liquors gave an additional one part of material with slightlylower melting point, totaling 9.3 parts. An additional crystallizationfrom methanol provided the analytical sample M.P. about 2l4-2l6 C. Thespecific optical rotation was 70.4 measured in chloroform (ca. 1 g./ 100ml. concentration).

The 17a-hydroxy-3-ethelene dioxy-6-methylpregn-5-en- 20-one showed ahigh antiestrogen and antiandrogen activity comparable to the product ofExample I, with a lesser progestational activity.

Example III 10 parts of 17a=acetoxy-6a-methylprogesterone were ketalizedin Z-methyl-Z-ethyl-1,3-dioxolane according to the method described inExample II. The recrystallization in methanol produced as crude product,9.1 parts of 17a acetoxy 3ethylenedioxy-6 methy1pregn-5 -en-20-one witha melting point about C.

Example IV '10 parts of 2l-fluoro-l7aacetoxy-6a-methyl progesterone(obtained as described by C. Bergstrom, P. B. Soleman, R. Nicholson, R.M. Dodson: J. Am. Chem. Soc. 82, 2322 (1960)) were ketalized in2-methyl-2-ethyl-l,3- dioxolane solution according to the methoddescribed in Example II. Addition of trace base (diethyl amine) to themethanol solvent used for crystallization was omitted. 8.9 parts ofl7a-acetoxy-3-ethylenedioxy-21-fiuoro-6- methylpregn-S-en-ZO-one wereobtained. Recrystallization from ether (a Soxhlet extractor was used)gave the analytical sample, which had a specific optical rotation ofabout 60 in chloroform solution (1 g./100 ml).

The infrared spectrum had its salient maxima at 3.40, 5.79, 5.81, 7.95,8.00, 9.32, 9.84 and 10.32 microns.

Example V 10 parts of l7a-hydroxy-2l-fiuoro-6a-methyl progesterone(obtained by the method of Bergstrom et al., 10c. cit.) were ketalizedin 2-methyl-2-ethyl-1,3-dioxolane solution according to the methoddescribed in Example II. Addition of trace base was omitted during theworkup, and potassium bicarbonate solution aqueous) was used during thewashing procedure. 8.5 parts of 17a-hydroxy-3-ethylenedioxy-21-fiuoro-6-methy1pregn-5-en 20 one were obtained, whichhad a specific optical rotation of about 81 in chloroform solution andshowed the fol lowing bands in the infrared region: 2.78, 3.40, 5.87,9.10, 9.90, 10.65 microns.

Example VI Example VII parts of 17u-hexanoyloxy-6a-methylprogesteroneprepared according to the above noted Babcock et al. technique weretreated according to Example I. The residue, however, failed to give acrystalline material. Therefore it was chromatographed on 250 partssilica gel (Davison 60-200) in benzene and eluted with benzene ethylacetate mixtures, each fraction with increasing concentration of ethylacetate. The fraction containing 10% ethyl acetate gave upon evaporationand crystallization of the semicrystalline residue (ether solution) 5parts of 17a-hexanoyloxy-3-ethylenedioxy-6-methylpregn 5 en- -one. Themelting point of this substance was about 93-99. As a proof of identityof this substance, 3 parts were dissolved in 60 parts of methanol andheated to reflux. Over a period of /2 hour a solution of potassiumhydroxide (0.35 part) in water (12 parts) was added in small portions attwo-minute intervals. The refluxing conditions were maintained duringthe addition and after completion of the addition for one hour. Thereaction mixture was condensed under reduced pressure to about half theoriginal volume. The crystallization which had started wascompleted byreposing the mixture in a freezer over night. The following morning thecrystals were filtered, washed with a little methanol/water (4:1), thenwith distilled water, dried and recrystallized from ether. 1.9 parts of17u-hydroxy-3-ethylenedioxy-6-methylpregn- 5-en-20-one were obtained,showing a melting point of about 2132l7 and a specific optical rotationof 69 in chloroform solution. The most salient bands in the infraredspectrum were: 2.79, 3.40, 5.92, 7.04, 9.10, 9.90, 10.25, 10.65 microns.This material was found identical with the compound obtained in ExampleII by mix melting point determination. Hydrolysis of the acyloxysubstituent at C-17 is a convenient way of preparing the 17-hydroxy-3-ethylene ketals when the ester (preferably the 17-acetate orpropionate) is available. However, when the 21-fluoro substituent ispresent, the so-called Favorski rearrangement is known to occur, andthis alkaline hydrolysis technique should be avoided.

Example VIII 10 parts of 6a-methyl-l7a-hexanoyloxy-2l-fiuoroprogesteronewere ketalized as described in Example V. There was obtained 6.5 partsof 17ix-hexanoyloxy-21- fluoro-3-ethylenedioxy-6-methylpregn-5-en-20one, showing an optical rotation of about -70 in chloroform. Salientinfrared bands were: 3.40, 5.78, 8.50, 9.10, 9.32, 9.88, 10.37 microns.

What is claimed is:

1. A compound of the structural formula References Cited by the ExaminerUNITED STATES PATENTS 4/1960 Gould et al 260239.55

OTHER REFERENCES LoeWent-hal: Tetrahedran, vol. 6, No. 4, pp. 269-303,pp. 287-295 relied on, June 1959. 1

LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE STRUCTURAL FORMULA